1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
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47<br />
Three similarly designed 6-month placebo-controlled trials form the basis of the<br />
approval of exenatide for use in patients with DM2 who exhibit unacceptable glycemic<br />
control while on metformin and/or a sulfonylurea testing the addition of exenatide to<br />
metformin alone, sulfonylurea alone, or metformin and a sulfonylurea together (166-168).<br />
The placebo-adjusted decline of HbA1c from baseline levels of 8.2 – 8.6% was ~1.0% in<br />
each trial. A mean placebo-adjusted weight loss of 2.5 kg occurred when exenatide was<br />
added to metformin, 1.0 kg when the drug was added to a sulfonylurea, and 0.9 kg when it<br />
was added to metformin plus a sulfonylurea. All patients began the treatment with 5 ug<br />
injected twice daily subcutaneously, before the morning and evening meals, for the first<br />
month, followed by 10 ug twice daily thereafter (166-168.) Following the 30- week,<br />
majority of the patients continued in an open-labeled extension for 82 weeks.<br />
A subset of 73 subjects from the exenatide + metformin and exenatide + metformin +<br />
sulfonylurea groups had post-prandial beta-cell function evaluated at baseline and after 6<br />
months (201). Glucose excursions after meal tolerance tests were significantly reduced after<br />
exenatide but not after placebo. To assess beta-cell function independent of confounding<br />
effects from post-prandial plasma glucose differences, mathematical modeling was<br />
performed incorporating 3 main components of beta-cell function: rate sensitivity (early<br />
insulin secretion rate [ISR]), dose- response relating ISR to plasma glucose concentration<br />
(glucose sensitivity) and a potentiation factor, which is a function of time and may reflect<br />
the actions of non-glucose secretagogues along with other factors (202). The mathematical<br />
model indicated a greater insulin response for any glucose concentration. Also, exenatide<br />
increased potentiation at 2-hour post meal compared with placebo, presumably due to its<br />
incretin effect since it is only partially affected while the beta-cell function is inherently<br />
impaired in DM 2 (203). In summary, exenatide enhanced post-prandial beta-cell function<br />
in patients with DM2 treated with metformin or metformin and sulfonylurea.<br />
It was demonstrated that intravenous exenatide enhanced first and second phase insulin<br />
secretion in response to an IV glucose bolus in subjects with DM2 treated with<br />
diet/exercise, metformin or acarbose and compared to healthy subjects with normal OGTT<br />
not receiving exenatide. Exenatide-treated patients with DM2 had a similar secretory<br />
pattern (first- and second-phase insulin secretion) but higher insulin levels than healthy<br />
subjects in contrast to patients with DM2 treated with placebo who had blunted first phase